Who is most likely to report side effects from taking statins? People who know they are taking statins and have read about side effects. As many as 20 percent of patients may stop taking or refuse the drug due to reported side effects, which include muscle pain, cataracts, memory loss, erectile dysfunction and disrupted sleep.
Yet in clinical trials people who don't know they are taking statins don't report side effects any more than a placebo group.
If you don't know, statins are cholesterol lowering drugs that are widely prescribed to patients at increased risk of heart attacks or strokes. A large review of evidence in The Lancet concluded that for every 10,000 people deemed high risk, lowering LDL cholesterol by 2 mmol/L with a daily dose of atorvastatin 40mg for 5 years could prevent 1,000 cases of heart attacks, strokes or coronary bypasses. Known side effects include an increase in the risk of diabetes (50-100 new cases per 10,000 people), hemorrhagic strokes (5-10 per 10,000) and myopathy (5 per 10,000). A contested issue is the rate of muscle pain and weakness, with observational studies in general practice finding that up to a fifth of patients report symptoms, which were not evident in randomized trials
Observational studies have confounders when it comes to high-profile topics, like this. Namely the nocebo effect.
Credit: Imperial College London
Professor Peter Sever, lead author from the National Heart and Lung Institute, Imperial College London, UK, says, “Just as the placebo effect can be very strong, so too can the nocebo effect. This is not a case of people making up symptoms, or that the symptoms are ‘all in their heads’. Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm. What our study shows is that it’s precisely the expectation of harm that is likely causing the increase in muscle pain and weakness, rather than the drugs themselves causing them.”
The first phase of the trial was conducted in 1998-2002 and included 10,180 patients aged 40-79 with hypertension and at least three other cardiovascular risk factors from the UK, Ireland and Scandinavia. Patients were randomly assigned to receive atorvastatin 10mg or placebo and were followed for 3 years. This phase was a blinded randomized trial: neither the doctors nor the participants knew whether they were receiving the drug or a placebo.
At the end of the 3 years, the drug was shown to be effective and the same patients were offered the choice of taking a statin or not. This is the non-blinded, non-randomized phase of the trial. 9899 of the original participants were followed for a further 2 years, and two thirds (65%) of them chose to use a statin.
During the blinded phase of the study, the rate of muscle-related symptoms was similar whether patients received a statin or placebo (2.03% per year vs. 2% respectively). However, during the non-blinded phase of the study, muscle-related symptoms were 41% more common among people taking statins compared to those who weren’t (1.26% vs 1.00% per year respectively).
In total, the analysis looked at 26 types of side effects including erectile dysfunction, sleep disturbance and cognitive impairment. These four side effects had previously been identified as possible side effects by the Medicines and Healthcare Products Regulatory Agency and Food and Drug Administration, on the basis of observational studies.
The randomized, blinded phase of the trial found no difference between the statin and placebo groups for erectile dysfunction (1.86% vs 2.14% per year). Sleep disturbance was lower in the statins group compared to placebo (1.00% vs 1.46%) and there was an increase in renal and urinary side effects in the statins group compared to placebo (1.87% vs 1.51%), both of which require further investigation. Too few cases of cognitive impairment were reported to provide reliable data, and no other differences in the other adverse events was identified.
The authors highlight that the trial was conducted in 1998-2004, before claims that statin therapy causes high rates of side effects were as widespread as they are today. They note that this may mean the strength of the nocebo effect is likely underestimated in this trial.
Participants were prescribed atorvastatin at a daily dose of 10mg, and only a few people in the non-blinded phase used simvastatin. This dose would now be considered a low dose, but the authors note that randomized trials of higher doses have not found that statins cause an increase in muscle related symptoms, other than the very small increase in myopathy.